RELAÇÃO ENTRE A DOENÇA PERIODONTAL E AS...
Transcript of RELAÇÃO ENTRE A DOENÇA PERIODONTAL E AS...
UNIVERSIDADE DE LISBOA
FACULDADE DE MEDICINA DENTÁRIA
RELAÇÃO ENTRE A DOENÇA PERIODONTAL E AS
PATOLOGIAS CARDIOVASCULARES
Catarina Maria da Silva Bernardes
MESTRADO INTEGRADO
2012
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UNIVERSIDADE DE LISBOA
FACULDADE DE MEDICINA DENTÁRIA
RELAÇÃO ENTRE A DOENÇA PERIODONTAL E AS
PATOLOGIAS CARDIOVASCULARES
Catarina Maria da Silva Bernardes
Dissertação orientada pela Sra. Dra. Susana Noronha
MESTRADO INTEGRADO
2012
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AGRADECIMENTOS
À Dr.ª Susana Noronha pela sua disponibilidade, ajuda e confiança, sem as quais
a elaboração desta dissertação não seria possível.
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DEDICATÓRIA
Em primeiro lugar aos meus pais por toda a sua dedicação e esforço em me
educar da melhor forma possível e por me terem transmitido os valores que permitiram
ser o que sou hoje. Tenho ainda a agradecer-lhes todo o apoio e a presença constante
nos bons e maus momentos, mostrando-me sempre qual o melhor caminho a seguir e
estimulando-me a tomar as melhores decisões.
A toda a minha família pelo esforço em compreender as minhas ausências, em
alguns momentos, e que sempre me transmitiram confiança necessária para ultrapassar
algumas adversidades.
Em jeito especial ao meu avô que, infelizmente, não pode estar presente para
assistir ao início da minha vida profissional, mas que sempre se mostrou muito
orgulhoso com os seus netos.
A todos os meus amigos que me acompanharam na minha vida académica e que
sempre me proporcionaram bons momentos, permitindo-me abstrair de alguns menos
bons.
À minha dupla de trabalho da FMDUL, Rita Reis pela sua amizade e pelo apoio
incondicional que sempre me prestou.
À Rita Moio por estes seis anos de amizade que fizeram toda a diferença na
minha vida.
Ao Manel por tudo o que fez e faz por mim e por ser o pêndulo da balança
necessário para alcançar o equilíbrio.
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RESUMO
A doença periodontal e as patologias cardiovasculares apresentam uma etiologia
complexa e multifatorial, sendo parte desta causada por fatores de risco.
A relação entre estas duas patologias tem sido especulada há aproximadamente
três décadas, contudo, esta eventual relação permanece controversa entre os diversos
estudos epidemiológicos realizados até à data.
Com o objetivo de procurar esclarecer uma eventual relação, entre as duas
patologias, foram propostas e descritas três teorias: teoria infeciosa ou bacteriana, teoria
inflamatória e a teoria imunológica.
No entanto, a associação causal entre a doença periodontal e os eventos
cardiovasculares continua a ser posta em causa visto alguns fatores de risco tradicionais
para as patologias cardiovasculares serem comuns aos da doença periodontal, bem
como, devido à presença de modificadores do efeito, dos próprios fatores de risco, e de
uma eventual relação bidirecional.
A influência do tratamento da doença periodontal na melhoria, ou agravamento,
do estado inflamatório sistémico e na prevenção de futuros eventos cardiovasculares é
igualmente controversa.
Os estudos realizados nesta temática apresentam diversas limitações e grande
heterogeneidade, nomeadamente, quanto à sua metodologia e amostras analisadas
carecendo de evidência científica. Deste modo, são necessários mais estudos futuros, a
longo prazo, nomeadamente estudos longitudinais, que permitam esclarecer o
mecanismo concreto responsável por esta relação, bem como, a postura mais correta
para o médico dentista adotar aquando do tratamento de pacientes com patologia
cardiovascular ou com risco de vir a desenvolvê-la futuramente.
Palavras-chave: doença periodontal, doenças cardiovasculares, aterosclerose,
fator de risco e indicador de risco.
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ABSTRACT
Periodontal disease and cardiovascular diseases have a complex and
multifactorial etiology, being part of this, caused by risk factors.
The relationship between these two diseases has been postulated for nearly three
decades, however, this possible relationship remains controversial among several
epidemiological studies conducted to date.
In order to seek to clarify a possible relationship between the two diseases it has
been proposed and described three theories: the bacterial or infectious theory, the
inflammatory theory and the immunological theory.
However, a causal association between periodontal disease and cardiovascular
events continues to be challenged because some traditional risk factors for
cardiovascular diseases are common to periodontal disease, as well as due to the
presence of effect modification of their own risk factors, and a possible bidirectional
relationship.
The influence of the treatment of periodontal disease in improving or worsening,
the systemic inflammatory state and in the prevention of the future cardiovascular
events is also controversial.
Studies on this topic have several limitations and heterogeneity, in particular,
regarding its methodology and samples lacking scientific evidence. Thus, further long
term studies are needed, namely longitudinal studies, to clarify the mechanism
responsible for this particular relationship, as well as the correct posture for the dentist
to adopt when treating patients with cardiovascular disease or risk of developing it in
the future.
Key-words: periodontal disease, cardiovascular diseases, atherosclerosis, risk
factor and risk indicator.
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LISTA DE ABREVIATURAS
Aa Aggregatibacter actinomycetemcomitans
ADN Ácido desoxirribonucleico
AR Alisamento radicular
AVC Acidente vascular cerebral
CBS Células brancas sanguíneas
CV Cardiovascular
DAC Doença arterial coronária
DCC Doença cardíaca coronária
DCV Doenças cardiovasculares
DP Doença periodontal
EAM Enfarte agudo do miocárdio
EIM Espessura íntima média
Fn Fusubacterium nucleatum
HbA1C Hemoglobina A1C
HDL Lipoproteína de elevada densidade
HTA Hipertensão arterial
ICAM Molécula de adesão intercelular
Ig Imunoglobulina
IL Interleucina
LDL Lipoproteína de baixa densidade
Lp-PLA2 Lipoproteína associada à fosfolipase A2
LPS Lipopolissacárido
MCP Proteína quimiotática dos monócitos
M-CSF Fator de estimulação de colónias de macrófagos
MMP Metaloproteínase de matriz
PA Plasminogénio ativado
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PAF Fator ativador de plaquetas
PCR Proteína C reativa
Pg Porphyromonas gingivalis
PGE-2 Prostanglandina E2
Pi Prevotella intermedia
PMN Polimorfonucleares
PS Pressão sanguínea
SCA Síndrome coronário agudo
Td Treponema denticola
Tf Tannerella forsythia
TNF Fator de necrose tumoral
TP Tratamento periodontal
UD Ultrassonografia Duplex
VCAM Molécula de adesão vascular
VIH Vírus da Imunodeficiência Humana
VLDL Lipoproteína de muito baixa densidade
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ÍNDICE
RESUMO ........................................................................................................................ iv
ABSTRACT .................................................................................................................... v
1. Introdução.................................................................................................................. 1
2. Doença Periodontal ................................................................................................... 3
3. Doenças Cardiovasculares......................................................................................... 6
4. Relação entre DP e DCV ........................................................................................... 8
4.1.Teoria bacteriológica/ infeciosa .............................................................................. 8
4.2.Teoria inflamatória ............................................................................................... 10
4.3.Teoria Imunológica ............................................................................................... 12
5. Fatores de risco comuns, modificadores do efeito e relação bidirecional ............... 13
6. Parâmetros bioquímicos e auxiliares de diagnóstico............................................... 19
7. Efeitos do tratamento periodontal na patologia cardiovascular .............................. 22
8. Discussão ................................................................................................................. 27
9. Conclusão ................................................................................................................ 31
REFERÊNCIAS BIBLIOGRÁFICAS ........................................................................ ix
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REFERÊNCIAS BIBLIOGRÁFICAS
Aggelopoulos P. et al. Comparative value of simple inflammatory markers in the
prediction of left ventricular systolic dysfunction in post acute coronary syndrome
patients. Mediators Inflamm 2009; 2009:826297.
Al-Emadi A. et al. Systemic diseases among patients with and without alveolar bone
loss. Quintessence Int 2006;37(10):761-765.
Almog DM. et al. Evaluation of a training program for detection of carotid artery
calcifications on panoramic radiographs. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2000;90(1):111-117.
Al-Zahrani MS, Bissada NF, Borawskit EA. Obesity and periodontal disease in
young, middle-aged, and older adults. J Periodontol 2003;74(5):610-615.
Amabile N. et al. Severity of periodontal disease correlates to inflammatory systemic
status and independently predicts the presence and angiographic extent of stable
coronary artery disease. J Int Med 2008;263(6):644-652.
American Academy of Periodontology. Consensus report for periodontal diseases:
epidemiology and diagnosis. Ann of periodontal 1996;1(1):221-2.
Andriankaja OM et al. Periodontal disease and risk of myocardial infarction: the role
of gender and smoking. Eur J Epidemiol 2007;22(10):699-705.
Ansai T. et al. Relationship between tooth loss and mortality in 80-year-old Japonese
community-dwelling subjects. BMC Public Health 2010;10:386.
Armitage GC, Robertson PB. The biology, prevention, diagnosis and treatment of
periodontal diseases: Scientific advances in the United States. JADA 2009;140(9):36S-
43S.
Armitage GC. Diagnosis of periodontal Diseases. J Periodontol 2003;74(8):1237-1247.
Arne S. et al. Identification of a Shared Genetic Susceptibility for Coronary Heart
Diseases and Periodontitis. PLoS Genetics 2009;5(2):e1000378.
Bahekar A. et al. The Prevalence and incidence of coronary heart disease is
significantly increased in periodontitis: A meta-analysis. Am Heart J 2007;
154(5):8307.
Ballanyne C.M. et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-
reactive protein, and risk for incident coronary heart disease in middle-aged men and
women in the Atherosclerosis Risk Communities (ARIC) study. Circulation 2004;
109(7):837-842.
x
Beck J. et al. Periodontal disease and cardiovascular disease. J Periodontol 1996;
67(10):1123-1137.
Beck JD, et al. Relationship of Periodontal Disease to Carotid Artery Intima-Media
Wall Thickness: The Atherosclerosis in Communities (ARIC) Study. Arterioscler
Thromb Vasc Biol 2001; 21(11):1816-1822.
Beck JD, Offenbacher S. Oral Health and Systemic Disease: Periodontitis and
Cardiovascular Disease. J Dent Educ 1998; 62(10):859-870.
Beck JD. et al. Periodontal Disease and Coronary Heart Disease: A Reappraisal of the
Exposure. Circulation 2005;112(1):19-24.
Beck JD. et al. The Periodontitis and vascular Events (PAVE) Pilot Study: Adverse
Events. J Periodontol 2008;79(1):90-96.
Beck JD. Risk revisited. Community Dent Oral Epidemiol 1998; 26:220-25.
Bergström J. Tobacco smoking and chronic destructive periodontal disease.
Odontology 2004;92(1):1-8.
Blaizot A. et al. Periodontal diseases and cardiovascular events: meta-analysis of
observational studies. Intern Dent J 2009; 59(4):197-209.
Bouchard P. et al. European Workshop in periodontal health and cardiovascular
disease consensus document. Eur Heart Journal Suppl 2010; 12(B):13-22.
Briggs JE et al. Angiographically confirmed coronary heart disease and periodontal
disease in middle-aged males. J Periodontol 2006; 77(1):95-102.
Buhlin K. et al. Periodontitis is associated with angiographically verified coronary
artery disease. J Clin Periodontol 2011; 38(11):1007-1014.
Buhlin K. Risk factors for cardiovascular disease in patients with periodontitis. Eur
Heart J 2003; 24(23):2099-2107.
Burke GL. et al. Arterial wall thickness is associated with prevalent cardiovascular
disease in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study.
Stroke 1995; 26(3):386-391.
Christan C. et al. White blood cell count in generalized aggressive periodontitis after
non-surgical therapy. J Clin Periodontol 2002; 29(3):201-206.
Chu X. et al. In vitro alteration of macrophage phenotype and function by serum
lipids. Cell Tissue Res 1999; 296(2):331-337.
Chun Y-HP. et al. Biological foundation for periodontitis as a potential risk factor for
atherosclerosis. J Periodont Res 2005; 40(1):87-95.
xi
Consensus Report Periodontal Diseases: Epidemiology and Diagnosis. Annals of
Periodontology 1996; 1(1):216-222.
Cotti E. et al. Can a chronic dental infection be considered a cause of cardiovascular
disease? A review of the literature. International Journal of Cardiology 2010;
148(2011):4-10.
Cueto A. et al. Periodontitis as risk factor for acute myocardial infarction. A case
control study of Spanish adults. J Periodont Res 2005; 40(1):36-42.
Cutler CW et al. Impaired bactericidal activity of PMN from two brothers with
necrotizing ulcerative gingivo-periodontitis. J Periodontol 1994; 65(4):357-363.
D´Aiuto F, Ready D, Tonetti MS. Periodontal disease and C-reactive protein-
associated cardiovascular risk. J Periodont Res 2004; 39(4):236-241.
D´Aiuto F. et al. Association of the metabolic síndrome with severe periodontitis in
large U.S. population-based survey. J Clin Endocrinol Metab 2008; 93(10):3989-3994.
D´Aiuto F. et al. Periodontitis and Systemic Inflammation: Control of the Local
infection is Associated with a Reduction in Serum Inflammatory Markers. J Dent Res
2004; 83(2):156-160.
D´Aiuto F. et al. Periodontal infections cause changes in traditional and novel
cardiovascular risk factors: Results from a randomized controlled clinical trial. Am
Heart J 2006;151(5):977-84.
D’Auito F et al. Periodontal therapy: a novel non-drug-induced experimental model to
study human inflammation. J Periodontol Res 2004; 39(5):294-299.
Danesh J. et al. Association of fibrinogen; C-reactive protein, albumin, or leukocyte
count with coronary heart disease: Meta-analyses of prospective studies. JAMA 1998;
279:1477-82.
DaSilva AM, Newman HN, Oakley DA. Psychosocial factors in inflammatory
periodontal diseases. A review. J Clin Periodontol 1995; 22(7):516-526.
Deans KA. et al. Differences in atherosclerosis according to area level socioeconomic
deprivation: cross sectional, population based study. BMJ 2009; 339:b4170.
Demmer RT, Desvarieux M. Periodontal infections and cardiovascular disease: The
heart of matter. JADA 2006; 137(10):14-20.
Demmer RT. et al. Evaluating clinical periodontal measures as surrogates for bacterial
exposure: The Oral Infections and Vascular Disease Epidemiology Study (INVEST).
BMC Medical Research Methodology 2010; 10:2.
xii
DeStefano F. et al. Dental disease and risk of coronary heart disease and mortality.
BMJ 1993; 306(3879):688-691.
Desvarieux M. et al. Periodontal microbiota and carotid intima-media thickness: the
Oral Infections and Vascular Disease Epidemiology Study (INVEST). Circulation 2005;
111(5):576-82.
Desvarieux M. et al. Relationship Between Periodontal Disease, Tooth Loss, and
Carotid Artery Plaque: The Oral Infections and Vascular Disease Epidemiology Study
(INVEST). Stroke 2003; 34(9):2120-2125.
Dorn JM. et al. Periodontal Disease and Recurrent Cardiovascular Events in survivors
of myocardial Infaction (MI): The Western New York Acute MI Study. J Periodontol
2010; 81(4):502-511.
Doxey DL et al. Platelet-derived growth factor levels in wounds of diabetic rats. Life
Sci 1995; 57(11):1111-1123.
Ebersole JL. et al. Systemic acute-phase reactants, C-reactive protein and haptoglobin,
in adult periodontitis. Clin Exp Immunol 1997; 107(2):347-352.
Elkaim R. et al. P. gingivalis Regulates the Expression of Cathepsin B and Cystatin C.
J Dent Res 2008; 87(10):932-936.
Elkaim R. et al. Prevalence of periodontal pathogens in subgingival lesions,
atherosclerotic plaques and healthy blood vessels: a preliminary study. J Periodont Res
2008; 43(2):224-231.
Engstrom G, Melander O, Hedblad B. Leukocyte count and incidence of
hospitalizations due to heart failure. Circ Heart fail 2009;2:217-222.
EUROASPIRE study group. A European Society of Cardiology survey of secondary
prevention of coronary heart disease: Principal results. Eur Heart J 1997; 18:1569-1582.
Fentoglu O, Bozkurt FY. The Bi-Directional Relationship between Periodontal
Disease and Hyperlipidemia. Eur J Dent 2008;2(2):142-6.
Fisher MA, Borgnakke WS, Taylor GW. Periodontal disease as a risk marker in
coronary heart disease and chronic kidney disease. Curr Opin Nephrol Hypertens. 2010;
19(6):519-526.
Ford P. et al. Characterization oh Heat Shock Protein-Specific T Cells in
Atherosclerosis. Clin Diagn Lab Immunol 2005; 12(2):259-267.
Freymiller EG, Sung EC, Friedlander AH. Detection of radiation-induced cervical
atheromas by panoramic radiography. Oral Oncol 2000; 36(2):175-179.
xiii
Friedewald VE. et al. The American Journal of cardiology and journal of
periodontology Editor´s Consensus: Periodontitis and Atherosclerotic Cardiovascular
Disease. J Periodontol 2009; 80(7):1021-1032.
Friedlander AH, Maeder LA. The prevalence of calcified carotid artery atheromas on
the panoramic radiographs of patients with type 2 diabetes mellitus. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 2000;89(4):420-424.
Friedlander AH. Panoramic radiography: the differential diagnosis of carotid artery
atheromas. Spec Care Dentist 1995; 15(6):223-227.
Frostegard J. SLE, Atherosclerosis and Cardiovascular Disease. J Intern Med 2005;
257(6):485-495.
Fukuchi Y. et al. Immunohistochemical Detection of Oxidative Stress Biomarkers,
Dityrosine and Ne-(Hexanoyl)Lysine, and C-Reactive Protein in Rabbits Atherosclerotic
Lesions. J Atheroscler Thromb 2008; 15(4):185-192.
Gaetti-Jardim E. et al. Quantative detection of periodontopathic bacteria in
atherosclerotic plaques from coronary arteries. J Med Microbiol 2009;58(12):1568-75.
Genco RJ et al. A proposed model linking inflammation to obesity, diabetes, and
periodontal infections. J Periodontol 2005;76(11):2075-2084.
Giannessi D. et al. Circulating heat chock proteins and inflammatory markers in
patients with idiopathic left ventricular dysfunction: their relationships with myocardial
and microvascular impairment. Cell Stress Chaperones 2007;12(3):265-274.
Grau AJ. et al. Association Between Acute Cereberovascular Ischemia and Chronic
and Recurrent Infection. Stroke 1997; 28(9):1724-1729.
Grau AJ. et al. Periodontal disease as a risk factor for ischemic stroke. Stroke 2004;
35(2):496-501.
Greenstein G, Hart TC. A critical assessment of interleukin-1(IL-1) genotyping when
used in a genetic susceptibility test for severe chronic periodontitis. J Periodontol 2002;
73(2):231-247.
Haraszthy VI. et al. Identification of periodontal pathogens in atheromatous plaques. J
Periodontal 2000;71(10):1554-1560.
Hernan MA. et al. Causal Knowledge as a prerequisite for confounding evaluation: an
application to birth defects epidemiology. Am J Epidemiol 2002; 155(2):176-184.
Higashi Y. et al. Periodontal Infection Is Associated With Endothelial Dysfunction in
Healthy Subjects and Hypertensive Patients. Hypertension 2008; 51(2):446-453.
xiv
Hoffman M. et al. Leukocytes and coronary heart disease. Atherosclerosis 2004;
172(1):1-6.
Hoke M. et al. The impact of dental disease on mortality in patients with asymptomatic
carotid artherosclerosis.Swiss Med Wkly 2011;141:w13236.
Holmlund A, Holm G, Lind L. Number of Teeth as a Predictor of Cardiovascular
Mortality in a Cohort of 7,674 Subjects Followed for 12 Years. J periodontal 2010;
81(6):870-876.
Holmlund A, Holm G, Lind L. Severity of periodontal disease and number of
remaining teeth are related to the prevalence of myocardial infarction and hypertension
in a study based on 4,245 subjects. J Periodontol 2006; 77(7):1173-1178.
Howell TH et al. Periodontal disease and risk subsequent cardiovascular disease in U.S.
male physicians. J Am Coll Cardiol 2001; 37(2):445-50.
Huck O. et al. Evaluating periodontal risk for patients at risk of or suffering from
atherosclerosis: Recent biological hypothesis and therapeutic consequences. Archives of
Cardiovascular Disease 2011;104(5):352-358.
Hujoel PP. et al. An exploration of the periodontitis-cancer association. Ann Epidemiol
2003; 13(5):312-316.
Hujoel PP. et al. Periodontitis-systemic disease associations in the presence of
smoking-causal or coincidental? Periodontol 2000 2002;30:51-60.
Hujoel PP. et al. Examining the link between coronary heart disease and the
elimination of chronic dental infections. J Am Dent Assoc 2001; 132(7):883-89.
Humphrey L. et al. Periodontal Disease and Coronary Heart Disease Incidence: A
systemic Review and Meta-analysis. J Gen Intern Med 2008; 23(12):2079-86.
Hyman J. The importance of assessing confounding and effect modification in research
involving periodontal disease and systemic diseases. J Clin Periodontol 2006;
33(2):102-103.
Hyman JJ, Winn DM, Reid BC. The role of cigarette smoking in the association
between periodontal disease and coronary heart disease. J Periodontol 2002, 73(9):988-
994.
Iacopino AM, Cutler CW. Pathophysiological relationships between periodontitis and
systemic disease: recent concepts involving serum lipids. J Periodontol 2000;
71(8):1375-1384.
xv
Ide M et al. The short-term effects of treatment of chronic periodontitis on circulating
levels of endotoxin, C-reactive protein, tumor necrosis factor-alpha, and interleukin-6. J
Periodontol 2004; 75(3):420-428.
Ide M. et al. Effect of treatment of chronic periodontitis on levels of serum markers of
acute-phase inflammatory and vascular responses. J Clin Periodontol 2003; 30(4):334-
340.
Imamura T. et al. Activation of Human Prothrombin by Arginine-specific Cysteine
Proteinases (Gingipains R) from Porphyromonas gingivalis. JBC 2001; 276(22):18984-
18991.
Janket S. Oral infection, hyperglycemia, and endothelial dysfunction. Oral Surg Oral
Med Oral Radiol Endod 2008; 105(2):173-179.
Janket SJ. et al. Meta-analysis of periodontal disease and risk of coronary heart disease
and stroke. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 95(5):559-69.
Jimenez M. et al. Periodontitis and incidence of cereberovascular disease in men. Ann
Neurol 2009; 66(4):505-12.
Joshipura K. et al. Strength of evidence Realting Periodontal Disease and
Atherosclerotic Disease. Compend Contin Educ Dent 2009:30(7):430-439.
Joshipura KJ. et al. Periodontal disease, tooth loss, and incidence of ischemic stroke.
Stroke 2003; 34(1):47-52.
Joshipura KJ. et al. Poor Oral Health and Coronary Heart Disease. J Dent Res 1996;
75(9):1631.
Kebschull M, Demmer RT, Papapanou PN. “Gum Bug, Leave My Heart Alone!”-
Epidemiologic Linking Periodontal Infections and Atherosclerosis. J Dent Res 2010;
89(9):879-902.
Kerrigan SW. et al. Role of Streptococcus gordonii surface proteins SspA/SspB and
Hsa in platelet function. Infect Immun 2007; 75(12):5740-7.
Khader YS,Albashaireh ZSM, Alomari MA. Periodontal Diseases and Risk of
Coronary Heart and Cerebrovascular Diseases: A Meta-Analysis. J Periodontol 2004;
75(8):1046-1053.
Khot UN. et al. Prevalence of conventional risk factos in patients with coronary heart
disease. JAMA 2003; 290(7):898-904.
Kiane D, Bouchard P. Periodontal diseases and health: Consensus Report of the Sixth
European Workshop on periodontology. J clin Periodontol 2008; 35(8):333-337.
xvi
Kiechl S. et al. Chronic and the Risk of Carotid Atherosclerosis: Prospective Results
from a Large Population Study. Circulation 2001; 103(8):1064-1070.
Kiane DF, Hart TC. Genes and gene polymorphisms associated with periodontal
disease. Crit Rev Oral Biol Med 2003;14(6):430-439.
Kocgozlu L. et al. Variable Cell Responses to P. gingivalis lipopolysaccharide. J Dent
Res 2009; 88(8):741-745.
Kuramitsu HK. et al. Role for Periodontal Bacteria in Cardiovascular Disease. Ann
Periodontol 2001;6(1):41-47.
Lalla E. et al. Oral Infection With Periodontal Pathogen Accelerates Early
Atherosclerosis in a Apoliprotein E- Null Mice. Arterioscler Thromb Vasc Biol 2003;
23(8):1405-1411.
Lam OL et al. A systematic review of the effectiveness of oral health promotion
activities among patients with cardiovascular disease. Int J Cardiol 2011; 151(3):261-
267.
Lamb DJ, El-Sankary W, Ferns GAA. Molecular mimicry in atherosclerosis: a role
for heat shock proteins in immunization. Atherosclerosis 2003; 167(2):177-185.
Leishman SJ, Do HL, Ford PJ. Cardiovascular disease and the role of oral bacteria.
Journal of Oral Microbiology 2010; 2:5781.
LeReche L, Dworkin SF. The role of stress in inflammatory disease, including
periodontal disease: review of concepts and current findings. Periodontol 2000 2002;
30:91-103.
Li L. et al. Porphyromonas gingivalis Infection Accelerates the Progression of
Atherosclerosis in a Heterozyghous Apolipoprotein E – Deficient Murine Model.
Circulation 2002; 105(7):861-867.
Loos BG et al. Elevation of systemic markers related to cardiovascular diseases in the
peripheral blood of periodontitis patients. J Periodontol 2000; 71(10):1528-1534.
Loos BG. Systemic Markers of Inflammation in Periodontitis. J Periodontol 2005;
76(11):2106-2115.
López NJ. et al. Effects of periodontal therapy on markers of systemic inflammation in
patients with coronary heart disease risk. Rev Med Chile 2009; 137(10):1315-1322.
Lösche W. et al. Lipoprotein-associated phospholipase A2 and plasma lipids in patients
with destructive periodontal disease. J Clin Periodontol 2005; 32(6):640-644.
Malthaner SC et al. Investigation of the association between angiographically defined
coronary artery disease and periodontal disease. J Periodontol 2002; 73(10):1169-1176.
xvii
Mattila K. et al. Association between dental health and acute myocardial infarction. Br
Med J 1989; 298:779-82.
Mayr M. et al. Endothelial cytotoxicity mediated by serum antibodies to heat shock
proteins of Escherichia coli and Clamydia pneumonia: Immune reactions to heat shock
protein as a possible link between infections and atherosclerosis. Circulation 1999;
99(12):1560-1566.
Mercanoglu F. et al. Endothelial Dysfunction in Patients With Chronic Periodontitis
and Its Improvement After Initial Periodontal Therapy. J Periodontol 2004;
75(12):1694-1700.
Meurman JH. et al. Dental infections and serum inflammatory markers in patients
with severe heart disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;
96(6):695-700.
Montebugnoli L. et al. Periodontal health improves systemic inflammatory and
haemostatic status in subjects with coronary heart disease. J Clin Periodontol 2005;
32(2):188-192.
Montebugnoli L et al. Poor oral health is associated with coronary heart disease and
elevated systemic inflammatory and haemostatic factors. J Clin Periodontol 2004;
31(1):25-29.
Morita M et al. Relationship between blood triglyceride levels and periodontal status.
Community Dent Health 2004; 21(1):32-36.
Mulligan R. et al. Baseline characteristics of participants in the oral health component
of the Women’s Interagency HIV Study. Community Dent Oral Epidemiol 2004;
32(2):86-98.
Mustapha Z. et al. Markers of systemic Bacterial Exposure in Periodontal Disease and
Cardiovascular Risk: A Systematic Review and Meta-Analysis. J Periodontol 2007;
78(12):2289-2302.
Nakib SA. et al. Periodontitis and Coronary Artery Calcification: The Atherosclerosis
Risk in Communities (ARIC) Study. J Periodontol 2004; 75(4):505-510.
Noack B et al. Metabolic diseases and their possible link to risk indicators of
periodontitis. J Periodontol 2000; 71(6):898-903.
Nonnenmacher C. Periodontal Microbiota in Patients With Coronary Artery Disease
Measured by Real-Time Polymerase Chain Reaction: A Case-Control Study. J
Periodontol 2007; 78(9):1724-1730.
xviii
Offenbacher S. Results From the Periodontitis and Vascular Events (PAVE) Study: A
Pilot Multicentre; Randomized; Controlled Trial to Study effects of periodontal Therapy
in a Secondary Prevention Model of Cardiovascular Disease. J Periodontal 2009;
80(2):190-201.
Papapanou PN. et al. Periodontal therapy alters gene expression of peripheral blood
monocytes. J Clin Periodontol 2007; 34(9):736-747.
BG Paraskevas S, Huizinga JD, Loos. A Systematic review and meta-analyses on C-
reactive protein in relation to periodontitis. J Clin Periodontol 2008; 35(4):277-290.
Pearson RW.et al. Markers of Inflammation and Cardiovascular Disease: Application
to clinical and Public Health Practice A Statement for Healthcare Professionals From
the Centers for Disease Control and Prevention and the American Heart Association.
Circulation 2003; 107(3):499-511.
Pereira RB. et al. Oral P. gingivalis infection alters the vascular reactivity in healthy
and spontaneously atherosclerotic mice. Lipids in Health and disease 2011; 10:80.
Pereira RM, de Carvalho JF, Bonfá E. Metabolic syndrome in rheumatological
diseases. Autoimmun Rev 2009; 8(5):415-419.
Persson GR, Persson RE. Cardiovascular disease and periodontitis: an update on the
associations and risk. J Clin Periodontol 2008; 35(8):362-379.
Persson RE. et al. Assessment of periodontal conditions and systemic disease in older
subjects. J Clin Periodontol 2002; 29(9):803-810.
Petty GW. et al. Ischemic Stroke Subtypes: A Population-Based Study Incidence and
Risk Factors. Stroke 1999 (12); 30:2513-2516.
Piconi S. et al. Treatment of periodontal disease results in improvements in endothelial
dysfunction and reduction of the carotid intima-media thickness. FASEB J. 2009;
23(4):1196-1204.
Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet 2005;
366(9499):1809-20.
Pussinen PJ et al. Systemic exposure to Porphyromonas gingivalis predicts incident
stroke. Atherosclerosis 2007; 193(1):222-228.
Pussinen PJ. et al. Antibodies to Periodontal Pathogens and Stroke Risk. Stroke 2004;
35(9):2020-2023.
Pussinen PJ. et al. Antibodies to Periodontal Pathogens Are Associated With Coronary
Heart Disease. Arterioscler Thromb Vasc Biol. 2003; 23(7):1250-1254.
xix
Pussinen PJ. et al. Endotoxemia, immune response to periodontal pathogens, and
systemic inflammation associate with incidence cardiovascular disease events.
Arteriosclerosis Thrombosis and Vascular Biology 2007; 27(6):1433-1439.
Pussinen PJ. et al. Periodontitis decreases the antiatherogenic potency of high density
lipoprotein. J Lipid Res 2004; 45:139-147.
Pussinen PJ. et al. Serum Antibody Levels to Actinobacillus actinomycetemcomitans
Predict the Risk for Coronary Heart Diseases. Arterioscler Thromb Vasc Biol. 2005;
25(4):833-838.
Pussinen PJ. et al. Severe periodontitis enhances macrophages activation via increased
serum lipopolysaccharide. Arterioscler Thromb Vasc Biol 2004; 24(11):2174-2180.
Ravon NA. et al. Signs of Carotid Calcification from Dental panoramic Radiographs
are in Agreement with Sonography Results. J Clin Periodontol 2003; 30(12):1084-1090.
Rech RL. et al. Association between periodontal disease and acute coronary syndrome.
Arquivos Brasileiros de Cardiologia 2007; 88(2):185-190.
Renvert S et al. Analysis of periodontal risk profiles in adults with or without a history
of myocardial infarction. J Clin Periodontol 2004; 31(1):19-24.
Renvert S. et al. Periodontitis: A Future Risk of Acute Coronary Syndrome? A Follow-
up Study over 3 years. J Periodontol 2010;81(7):992-1000.
Ridker PM et al. Reduction in C-reactive protein and LDL cholesterol and
cardiovascular event rates after initiation of rosuvastatin: a prospective study of the
Jupiter trial. Lancet 2009; 373(9670):1175-1182.
Ridker PM. et al. C- reactive protein and other markers of inflammation in the
prediction of cardiovascular disease in women. N Engl J Med 2000; 342:836-843.
Ridker PM. et al. Inflammation, Aspirin and the of Cardiovascular Diseases in a
Apparently Healthy Men. The New England Journal of Medicine 1997; 336(14):973-
979.
Ridker PM. et al. Plasma Concentration of Interleukin-6 and the Risk of Future
Myocardial Infarction Among Apparently Healthy Men. Circulation 2000;
101(15):1767-1772.
Roth GA et al. Porphyromonas gingivalis infection and cell death in human aortic
endothelial cells. FEMS Microbiol Lett. 2007; 272(1):106-113.
Roth GA. et al. Infection with periodontal pathogens increases mononuclear cell
adhesion to human endothelial cells. Atherosclerosis 2007; 190(2):271-281.
xx
Roth GA. et al. Porphyromonas gingivalis infection and cell death in human aortic
endothelial cells. FFEMS Microbiol Lett 2007; 272(1):106-13.
Roth GA. et al. Infection with periodontal pathogen induces procoagulant effects in
human aortic endothelial cells. J Thromb Haemost 2006; 4(10):2256-61.
Salzberg TN et al. C-Reactive protein levels in patients with aggressive periodontitis. J
Periodontol 2006; 77(6):933-939.
Sarlati F. et al. Relationship between obesity and periodontal status in a sample of
young Iranian adults. Int Dent J 2008; 58(1):36-40.
Scannapieco FA, Dasanayake AP, Chun N. “Does Periodontal Therapy Reduce the
Risk for Systemic Diseases?”. Dent Clin N Am 2010;54(1):163-181.
Schaefer AS. et al. Identification of a shared genetic susceptibility locus for coronary
heart disease and periodontitis. PLOS Genet 2009; 5(2):e1000378.
Schillinger T. et al. Dental and Periodontal Status and Risk for Progression of Carotid
Atherosclerosis: The Inflammation and Carotid Artery Risk for Atherosclerosis Study
Dental Substudy. Stroke 2006; 37(9):2271-2276.
Sesso HD. et al. C-reactive protein and the risk of developing hypertension. JAMA 290
(22):2945-2951.
Sfyroeras GS. et al. Association between periodontal disease and stroke. J Vasc Surg
2012; 55(4):1178-84.
Sidney C, Smith Jr. Current and Future Directions of Cardiovascular Risk Prediction.
Am J Cardiol 2006; 97(A):28-32.
Slade GD. et al. Relationship between periodontal disease and C-reactive protein
among adults in the atherosclerosis risk in communities study. Arch Intern Med 2003;
163(10):1172-1179.
Slim SJ et al. Periodontitis and the risk for non-fatal stroke in Korean adults. J
Periodontol 2008:79(9):1652-1658.
Socransky SS, Haffajee AD. Periodontal microbial ecology. Periodontology 2000
2005; 38:135-187.
Soskolne WA, Klinger A. The relationship between periodontal diseases and diabetes:
an overview. Ann Periodontol 2001; 6(1):91-98.
Spahr A. et al. Periodontal infections and coronary heart disease: role of periodontal
bacteria and importance of total pathogen burden in the Coronary Event and Periodontal
Disease (CORODONT) study. Arch Intern Med 2006; 166(5):554-9.
xxi
Sukhija R. et al. Inflammatory markers, angiographic severity of coronary artery
disease, and patient outcome. Am J Cardiol 2007; 99(7):879-884.
Taguchi A. et al. Tooth is associated with an increased risk of hypertension in
postmenopausal women. Hypertension 2004; 43:1297-300.
Taylor GW. Bidirectional interrelationships between diabetes and periodontal diseases:
an epidemiologic perspective. Ann Periodontol 2001; 6(1):99-112.
Teixeira J, Pinho M. Associação entre periodontite e acidente vascular cerebral
(AVC). Rev Port Estomatol Med Dent Cir Maxilofac. 2011; 52(2):115-121.
Thomopoulos C. et al. Peridontitis and coronary artery disease: a questioned
association between periodontal and vascular plaques Review article. Am J Cardiovasc
Dis 2011; 1(1):76-83.
Tiller R. et al. Association between carotid artery calcifications an periodontal risk: a
cross sectional study of panoramic radiographic findings. BMC Cardiovasc Disord
2011;11: 67.
Tonetti MS. et al. Treatment of Periodontitis and Endothelial Function. N Engl J Med
2007; 356(9):911-20.
Ushida Y et al. Changes in serum interleukin-6, C-reactive protein and
thrombomodulin levels under periodontal ultrasonic debridement. J Clin Periodontol
2008; 35(11):969-975.
Weyrich A, Zimmerman GA. Platelets: signaling cells in the immune continuum.
Trains Immunology 2004; 25(9):489-495.
Wilson PW. et al. Prediction of coronary heart disease using risk factor categories.
Circulation 1998; 97(18):1837-1847.
Woodward M. et al. A comparison of the associations between seven haemostatic or
inflammatory variables and coronary heart disease. J Thromb Haemost 2007;
5(9):1795-1800.
Wu T. et al. Periodontal disease and risk of cerebrovascular disease: the first national
health and nutrition examination survey and its follow-up study. Arch Intern Med
2000;160(18):2749-55.
Ylöstalo PV, Knuuttila ML. Confounding and effect modification: possible
explanation for variation involving periodontal disease and systemic diseases. J Clin
Periodontol 2006; 33(2):104-108.
Yoko OE. et al. Significant association between score of periodontal disease and
coronary artery disease. Heart Vessels 2009; 24(2):103-107.
xxii
Yoshida H, Kisugi R. Mechanisms of LDL oxidation. Clinica Chimica Acta
2010;411:1875-1882.